Novel mutation of TBX3 in a Japanese family with ulnar-mammary syndrome: Implication for impaired sex development

We report on a Japanese family (two brothers and their mother) with ulnar-mammary syndrome (UMS). Clinical features included hypoplasia or aplasia of upper limbs on the ulnar side in the three affected individuals, micropenis with or without cryptorchidism, and hypoplastic nipples in the brothers; and hypoplastic mammary glands and nipples, poor perspiration, and bicornuate uterus in the mother. Endocrine studies performed for the underdeveloped external genitalia when the brothers were 11 6/12 and 7 2/12 years old, respectively, indicated low to low-normal responses of luteinizing hormone (LH) and follicle stimulating hormone (FSH) to gonadotropin releasing hormone stimulation tests (elder brother: LH = < 0.2 → 2.2 IU/L, FSH = 0.6 → 2.2 IU/L; younger brother: LH = < 0.2 → 3.3 IU/L, FSH = 0.7 → 4.4 IU/L) and normal testosterone responses to human gonadotropin stimulation tests (elder brother: < 0.5 → 8.8 nmol/L; younger brother: < 0.5 → 6.3 nmol/L). Testosterone enanthate therapy (25 mg/dose IM twice) was effective in the brothers, with penile length increase being similar between the brothers (∼5 mm/dose) and 23 age-matched boys with idiopathic micropenis (mean 4.4 mm/dose, range 2.5-7.5 mm/dose). Sequence analysis of the TBX3 gene showed a novel heterozygous nonsense mutation (A817T, K273X) in exon 4 of the three patients. The results are consistent with the previous finding that UMS is caused by haploinsufficiency of TBX3, and imply that mild gonadotropin deficiency may be the primary cause for underdeveloped external genitalia in males with UMS.